MN is a cell surface protein that is detected in a number of clinical carcinoma samples but is absent in the normal tissue of the corresponding organs. The MN cDNA has been cloned (Pastorek, J. et al, Oncogene (1994), 9, 2877-2888) and the predicted protein consists of a signal peptide, a proteoglycan-related sequence, a carbonic anhydrase domain, a transmembrane segment, and a short intracellular tail. MN is normally expressed in stomach and bile duct mucosa (Liao, S. Y., et al, Am J Pathol (1994), 145, 598-609) and in highly proliferative normal cells located in the small intestine (Saarnio, J. et al, J Histochem Cytochem (1998) 46, 497-504). However, MN is ectopically expressed in 100% renal cell carcinomas (Liao, S. Y., Cancer Res (1997) 57, 2827-2831), 100% of carcinomas of the esophagus (Turner, J. R. Hum Pathol, (1997) 28, 740-744), greater than 90% of cervical carcinomas (Liao, S. Y., et al, Am J Pathol (1994), 145, 598-609), 76% of malignant colon carcinomas, (Saarnio, J. et al, Am J Pathol (1998) 153, 279-285), 80% of non-small cell lung carcinomas (Vermylen, P. et al, Eur Respir J (1999), 14, 806-811), and in 48% of breast cancers (Chia, S. K. et al, J. Clin. Oncol (2001) 19, 3660-3668).
Antibodies against MN have been described. Mouse monoclonal antibody G250 is effective in the reduction of renal cell carcinoma tumor size in a mouse model (van Dijk, J. et al, Int. J. Cancer (1994) 56, 262-268). This antibody was subsequently made into a chimeric antibody containing human Fc regions and the mouse variable regions. The chimeric G250 antibody is only 66% human, leading to a greater chance of immunogenicity in humans compared to a comparable fully human antibody. Therefore, treatment with the 33% mouse antibody may lead to a human anti-mouse immunogenic response, rendering the anti-cancer treatment ineffective. These problems with chimeric antibodies clearly raise the need for fully human antibodies against MN.